by Aly Muhammad Ladak

credit: Zayd Diz

Viruses are responsible for countless human diseases – from polio to smallpox, from ebola to the flu. Their impact on our lives has never been as clear as during the COVID-19 pandemic. Our main strategy for dealing with viruses, both historically and during this pandemic, has been vaccines – which prime the immune system to prepare for a future infection. However, similar to antibiotics, which combat bacterial infections, we also have antiviral drugs, which combat viral infections. These have a number of limitations, but are an increasingly promising form of treatment. To unravel this promise, we need to understand how they work.

What is a virus?

To understand why antiviral drugs face somewhat different challenges than, say, antibiotics, we first need to understand what a virus is. Believe it or not, viruses aren’t considered to be living things! In order to be classified as a living organism, something needs to be capable of performing metabolic functions and replicating its molecular components on its own. Viruses can’t do this – for them to thrive beyond their mere existence as chemical bundles, they need to infect host cells. This is part of why antivirals are so hard to make: whereas bacteria have unique molecular processes which we can target, viruses hijack our own cells and use our cellular machinery to carry out many of these processes. 

Viral life cycles

So, if viruses use our own cellular machinery to function, how can we attack them? Since we can’t counteract viruses by inhibiting our own cellular processes – that would be at our own detriment – we can instead stop them from spreading and infecting more cells. To do this, we need drugs that interfere with certain parts of a virus’ life cycle. 

There are three basic parts to a virus’ life cycle which can be targeted: entry into cells, replication, and exit from cells. We can categorize antivirals based on which part they target. For instance, viral entry generally requires the virus to attach to particular proteins on a cell’s surface – drugs can attach to these proteins and block key locations to prevent the virus from binding. This, for example, is how Bulevirtide – used to treat chronic Hepatitis D – reduces viral infections. Moreover, once a virus is in a cell, it needs to create copies of itself. Many antiviral drugs – including two antivirals shown to reduce COVID-19 severity – inhibit these replication processes. Finally, we can try to prevent viral exit, essentially trapping viruses inside the cells they are currently in. The effectiveness of this last method varies depending on the virus, but it does work well for some viruses – for instance, tamiflu (an antiviral used to treat influenza in those at high risk) stops new flu viruses from leaving infected cells.

When drugs don’t work: resistance and specificity

Unfortunately, most antimicrobial drugs – antiviral, antibiotic, or otherwise – won’t work forever. When we treat patients with them, some microbes are going to end up surviving, generating selective pressure for resistance to these drugs to arise. HIV is a particularly strong example of this: a number of drugs have been developed which inhibit the viral life cycle and halt disease progression, but the virus quickly evolves to become resistant. This is why the standard treatment for HIV is a three-drug ‘cocktail’ – even if the virus evolves resistance to one drug, the other drugs are still able to stop its spread.

Moreover, antivirals are generally far more specific drugs than antibiotics. For example, penicillin (prior to the emergence of resistance) could be used to treat many bacterial infections. These sorts of broad-spectrum treatments are lacking when it comes to viruses. Thus, for every new virus that emerges, we may have to develop new drugs.

Will they help us fight COVID-19?

Two drugs – molnupiravir (from Merck) and paxlovid (from Pfizer) – have recently been shown to be effective against COVID-19 infection. Both interfere with replication, but in different ways. Molnupiravir ‘pretends’ to be an RNA nucleotide (a building block of the virus’ genetic material), sneaking into newly-created copies of the virus and interfering with proper replication. Paxlovid, on the other hand, stops the function of an enzyme that helps process SARS-CoV-2 protein.

However, we still don’t know everything about these drugs. First, they were only tested in high-risk, unvaccinated populations, so we can’t be sure if these results are extendable to the broader population. Second, their side effects aren’t well characterized – molnupiravir, for instance, isn’t recommended for pregnant people, because we don’t know whether it can also introduce mutations into the fetus. Finally, we don’t know how rapidly SARS-CoV-2 will develop resistance to these drugs. But, if used wisely, and combined with continued vaccinations and public health efforts, there may finally be a way out of the pandemic.

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